Table 1. Summary of clinical features of families 1–11 with ANKRD11 mutations.
| Patient | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Feature | 1A (25 y) | 1B (14 y) | 1C (12 y) | 1D (7 y) | 1E (47 y) | 2 (12 y) | 3 (8 y) | 4 (25 y) | 5 (6 y) | 6 (38 y) |
| Gender | M | M | F | M | F | M | M | F | M | F |
| ANKRD11 mutation | c.7481 dup; p.(Pro2495fs) | c.7481 dup; p.(Pro2495fs) | c.7481 dup; p.(Pro2495fs) | c.7481 dup; p.(Pro2495fs) | c.7481 dup; p.(Pro2495fs) | c.4391_ 4392del; p.(Lys1464fs) | c.6184del; p.(Leu2062fs) | c.3123_ 3126del; p.(Ile1042fs) | c.1460_ 1463del; p.(Glu487fs) | c.1903_ 1907del; p.(Lys635fs) |
| Macrodontia upper central incisorsa | + | + | + | + | + | + | + | + | − | + |
| Additional dental abnormalities | ? | + | + | + | − | − | + | − | − | − |
| Characteristic facial appearancea | + | + | + | + | + | + | + | + | + | + |
| Hand anomaliesa | + | + | + | + | + | + | + | + | + | + |
| Postnatal short staturea | − (−1 SD) | − (−1.1 SD) | − (−0.5 SD) | − (−1.8 SD) | + (−3.5 SD) | + (−2.5 SD) | + (−4 SD) | − (−1.8 SD) | + (−3 SD) | + (−2.5 SD) |
| First degree relative with KBG syndr.a | + | + | + | + | + | − | − | − | − | − |
| Delayed bone agea | − | ? | ? | ? | ? | − | + | ? | + | ? |
| Costovertebral anomaliesa | + | − | − | − | + | − | − | ? | + | + |
| Neurological involvementa (ID and/or seizures) | ID Mod. | ID Mod. seizures | ID Mild–mod. seizures | ID Mild–mod. | ID Mild (IQ not tested) | ID Mild IQ 67 | IQ 75 Delayed SLD | Normal intelligence | Mild DD IQ not tested | ID Mod. |
| Behavioural abnormalities | ASD | ASD Hyperactivity | ASD | ASD Hyperactivity | Not tested | ASD Hyperactivity Aggressive behaviour | ADHD | Some features of ASD Anxious personality Difficulties in social behaviour | − | Compulsive behaviour |
| Cryptorchidism | + | + | NA | + | NA | − | − | NA | + | NA |
| Congenital heart defect | − | − | − | − | − | − | − | + VSD | − | − |
| Hearing loss | − | − | + | + | + | − | − | + | − | − |
| Palatal defects | − | − | − | ± | − | − | − | + | − | − |
| Additional features | BP | BP | BP | BP Strabismus Hypermetropia | Polyhydramnios Nocturnal enuresis Recurrent RTI GI reflux | Simian crease | BP Recurrent RTI Simian crease Perthes disease Narrow ear canals | Bil. Perthes disease | Large fontanelles at birth | |
| Patient | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Feature | 7A (9 y) | 7B (36 y) | 7C (28 y) | 8 (11 y) | 9 (10 y) | 10 (11 y) | 11 (19 y) | 12A (19 y) | 12B (41 y) | Total (published)b |
| Gender | M | F | F | M | F | M | M | F | F | 10 Males 9 Females |
| ANKRD11 mutation | c.3832 A>T; p.(Lys1278a) | c.3832 A>T; p.(Lys1278a) | c.3832 A>T; p.(Lys1278a) | c.2751 dup; p.(Glu918a) | c.3382_ 3383del; p.(Asp1128fs) | c.1903_ 1907del; p.(Lys635fs) | c.6513 dup; p.(Gly2172fs) | c.1318C>T; p.(Arg440a) | c.1318C>T; p.(Arg440a) | 19 (7) |
| Macrodontia upper central incisorsa | + | + | + | + | + | + | + | + | ? | 17/19 (6/7) |
| Additional dental abnormalities | − | − | + | + | + | + | ? | ? | Premature loss of teeth | 9/19 (NA) |
| Characteristic facial appearancea | + | + | + | + | + | + | + | + | + | 19/19 (7/7) |
| Hand anomaliesa | + | + | + | − | + | + | + | + | + | 18/19 (7/7) |
| Postnatal short staturea | + (−2.7 SD) | − (−0.5 SD) | + (−2 SD) | + (−3.5 SD) | + (−3 SD) | − (−0.75 SD) With GH | − (−1.8 SD) | + (−2.8 SD) | + (−3.4 SD) | 11/19 (6/7) |
| First degree relative with KBG syndr.a | + | + | + | − | − | − | − | + | + | 10/19 (3/7) |
| Delayed bone agea | ? | ? | ? | ? | − | + | ? | − | ? | 3/19 (4/7) |
| Costovertebral anomaliesa | − | − | + | − | + | + | + | + | ? | 9/19 (5/7) |
| Neurological involvementa (ID and/or seizures) | ID Seizures | LD | ID Mild Seizures | IQ 84 Delayed SLD | Mild ID IQ 68 | Mild ID Dyslexia Poor short-term memory | ID Mod. | ID Mod. | ID (IQ not tested) Seizures | 19/19 (7/7) |
| Behavioural abnormalities | ADHD ASD | Hyperactivity | Anxious personality | Aggressive behaviour ADHD ASD | Temper tantrums | Temper tantrums Impairment in communication skills Tics | ASD ADHD | Temper tantrums | Introvert personality | 18/19 (NA) |
| Cryptorchidism | + | NA | NA | − | NA | + | − | NA | NA | 6/10 (6/7) |
| Congenital heart defect | + VSD | − | + AVSD | − | − | − | − | − | − | 3/19 (0/7) |
| Hearing loss | − | − | − | − | + | − | + | − | − | 6/19 (NA) |
| Palatal defects | − | − | − | − | − | − | + | High-arched palate | ? | 2/19 (0/9) |
| Additional features | Congenital hip dysplasia | Umbilical hernia | Recurrent RTI | Simian crease Short tendons Limited rotation forearms Obesity Pineal cyst | Polyhydramnios Palatal asymmetry Slightly enlarged ventricles | Osteochondritis dissecans Hypertrophic scars Contractures Dysgenesis CC | Myopia Premature birth at 32 weeks | Myopia | 3/19 Hip anomaly 5/19 BP 3/19 Simian crease 2/19 Myopia | |
Abbreviations: ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; AVSD, atrioventricular septal defect; BP, breech position; CC, corpus callosum; DD, developmental delay; GH, growth hormone; ID, intellectual disability; LD, learning difficulties; NA, not applicable; RTI, respiratory tract infections; SLD, speech and language development; VSD, ventricular septal defect; VPI, velopharyngeal insufficiency.
Characteristic facial appearance is defined as the presence of at least one of the top three representative findings from at least three of the following six categories: (1) craniofacial shape: brachy/turricephaly, broad/round triangular face, and/or short/webbed neck (2) hirsutism: low hairline, broad/wide/bushy eyebrows and/or synophrys (3) eyes: hypertelorism/telecanthus, epicanthic folds and/or strabismus (4) ears: prominent/protruding ears, dysplastic helices/antihelices and/or hearing loss (5) nose: upturned nose/anteverted nostrils, large/bulbous nasal tip, and/or prominent nasal bridge (6) mouth: long/flat philtrum, thin upper lip, palatal irregularities. Postnatal short stature is defined as a height less than the 3rd centile or −2 SDs. Mutation nomenclature is according to the February 2009 Human reference sequence 37 (GRCh37/hg19), transcript NM001256182.1.
Major criteria according to Skjei et al.15